EP0392384B1 - Targeted forms of methyltrithio antitumor agents - Google Patents

Targeted forms of methyltrithio antitumor agents Download PDF

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Publication number
EP0392384B1
EP0392384B1 EP90106631A EP90106631A EP0392384B1 EP 0392384 B1 EP0392384 B1 EP 0392384B1 EP 90106631 A EP90106631 A EP 90106631A EP 90106631 A EP90106631 A EP 90106631A EP 0392384 B1 EP0392384 B1 EP 0392384B1
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EP
European Patent Office
Prior art keywords
formula
trivalent
divalent
compound
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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EP90106631A
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German (de)
English (en)
French (fr)
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EP0392384A2 (en
EP0392384A3 (en
Inventor
George A. Ellestad
William James Mcgahren
Martin Leon Sassiver
Philip R. Hamann
Lois M. Hinman
Janis Upeslacis
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Wyeth Holdings LLC
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American Cyanamid Co
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Priority claimed from US07/339,343 external-priority patent/US5053394A/en
Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Publication of EP0392384A2 publication Critical patent/EP0392384A2/en
Publication of EP0392384A3 publication Critical patent/EP0392384A3/en
Application granted granted Critical
Publication of EP0392384B1 publication Critical patent/EP0392384B1/en
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
    • A61K47/6809—Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention is disulfide compounds of the ⁇ 1 , ⁇ 2 , ⁇ 1 , ⁇ , and ⁇ N-acyl derivatives of the LL-33288 complex and derivatives thereof as well as the disulfide compounds of N-acyl derivatives of BBM-1675, FR-900405, FR-900406, PD114759, PD115028, CL-1577A, CL-1577B, CL-1577D, CL-1577E, CL-1724 antibiotics and derivatives thereof prepared by reacting the antibiotic with an unsubstituted or substituted alkyl mercaptan.
  • These disulfide compounds are effective antitumor agents.
  • the invention also describes carrier-drug conjugates of the disulfide analogs prepared from the materials listed above.
  • the carrier (targeting) portion of the conjugate is a mono- or polyclonal antibody, their fragments, chemically or genetically manipulated counterparts, or growth factors or steroids.
  • the invention includes the method of using the carrier-drug conjugates as well as their process of manufacture.
  • the family of antibacterial and antitumor agents known collectively as the LL-E33288 complex are described and claimed in EPO publication number 0182152A3 published May 28; 1986 and are used to prepare the disulfur antitumor agents which are some of the starting materials for targeted forms of the antitumor agents of our invention.
  • the EPO publication number 0182152A3 describes the LL-E33288 complex, the components thereof, namely, LL-E33288 ⁇ 1 Br , LL-E33288 ⁇ 1 I , LL-E33288 ⁇ 2 Br , LL-E33288 ⁇ 2 I , LL-E33288 ⁇ 1 Br , LL-E33288 ⁇ 1 I , ll-E33288 ⁇ 1 Br , LL-E33288 ⁇ 1 I and LL-E33288 ⁇ 1 I , and methods for their production by aerobic fermentation utilizing a new strain of Micromonospora echinospora ssp calichensis or natural or derived mutants thereof.
  • the EPO publication number 0182152A3 also discloses proposed structures for some of the above named components. These proposed structures are reproduced in Table 1
  • the N-acyl counterparts ⁇ 1 , ⁇ 2 , ⁇ 1 , ⁇ 1 , ⁇ of the LL-E33288 complex as well as the N-acyl counterparts BBM-1675, FR-900405, FR-900406, PD 114759, PD 115028, CL-1577A, CL-1577B, CL-1577D, CL-1577E and CL-1724 antibiotics each contain a methyltrithio group in their structure.
  • disulfides of the formula Q-Sp-SS-W are prepared from the antitumor antibiotics designated LL-E33288 (CH 3 SSS-W) wherein: R 5 is CH 3 , C 2 H 5 , or (CH 3 ) 2 ; X is an iodine or bromine atom; R 5 is a hydrogen or the group RCO, wherein R is hydrogen, CH 3 , or a mono-substituted aryl group; and Sp and Q are as hereinbefore defined.
  • Tu is a mono- or polyclonal antibody, its fragments, its chemically or genetically manipulated counterparts, or growth factors or steroids
  • Y is a side-chain amino, carboxy, or thiol group of a protein, an aldehyde derived from carbohydrate residues, or an amidoalkylthio group
  • n is an integer of from 1 to 100
  • the same randomly-substituted immunoconjugates can also be prepared from the 3-mercaptopropionic acid derivative using other carboxyl group activating agents such as a variety of carbodiimides, or the corresponding acyl azide.
  • Such functional groups are preferably, though not limited to, those which react with aldehydes under acidic aqueous conditions.
  • the reactivity of protein lysines under basic conditions is sufficiently great such that their amines compete with the products of Scheme II for available aldehydes of the monoclonal antibody.
  • Alternative aldehyde-reactive groups are, for example, the semicarbazide, the thiosemicarbazide, and the O-substituted hydroxylamine functionalities.
  • the targeting unit (Tu) can be first modified to contain a thiol group, which is then reacted with the compounds of Tables 1 and 2 in accordance with Scheme III below: wherein Tu, Y, Q, Sp, W, n, and m are as hereinbefore defined, and P is hydrogen or 2-(pyridylthio), with the proviso that when Y is a thiol derived from a backbone amino acid residue of Tu, Z-Sp taken together is a covalent bond.
  • sulfhydryl groups inherent within the structure of monoclonal antibodies in dimeric form as cystine residues can be used to participate in the reaction of Scheme III directly.
  • a preferred embodiment of targeted derivatives of this invention is a protein-drug conjugate of the formula: prepared from the class of antitumor antibiotics designated N-acyl LL-E33288 (CH 3 SSS-W) comprising:
  • MoAbs monoclonal antibodies
  • Lym 1 and Lym 2 recognize different antigens on mature B-lymphocytes and their product lymphomas. The production and characteristics of these MoAbs are described by A.L. Epstein, et. al., "Cancer Research” 47 , 830 (1987).
  • MoAb B72.3 targets primarily to carcinomas of the breast and colon, though reactivity with pancreatic, ovarian, and lung carcinomas has also been noted. The antibody has been described by T.L. Klug, et. al., "Int. J. Cancer” 38 , 661 (1986).
  • MoAb CT-M-01 which recognizes primarily breast tumors is described in EPO application 86 401482.4 filed July 3, 1986 and MAC-68 is produced by a sub-clone of the hybridoma which produces CT-M-01, and recognizes both breast and colon carcinomas.
  • the targeting units restricted only to monoclonal antibodies.
  • the compounds of this invention designated as Q-Sp-SS-W are active as antibacterial agents. Their in vitro antibacterial activity can be determined against gram-positive and gram-negative bacteria by a standard agar dilution method. Mueller-Hinton agar containing two-fold decreasing concentrations of the antibiotics is poured into petri dishes. The agar surfaces are inoculated with 1 to 5 x 10 4 colony forming units of bacteria by means of a Steers replicating device. The lowest concentration of compound that inhibits growth of a bacterial strain after about 18 hours of incubation at approximately 36 o C is recorded as the minimal inhibitory concentration (MIC) for that strain.
  • MIC minimal inhibitory concentration
  • the disulfide compounds described above are active antitumor agents.
  • the tumor transplant was by intraperitoneal injection of 0.5 ml of dilute ascitic fluid containing 1 x 10 6 cells of lymphocytic leukemia P388 on day zero.
  • the test compounds were administered intraperitoneally at a volume of 0.5 ml in sterile, pyrogen free saline on days 1, 5 and 9 (relative to tumor inoculation) at the indicated doses.
  • the median survival time and the ratio of survival time for treated (T)/control (C) animals were calculated. Values of T/C greater than or equal to 125 are considered to reflect significant antitumor activity.
  • Animals used can be BDF1 female mice. There are 5 or 6 mice per test group. A one gram portion of melanotic melanoma B16 tumor is homogenized in 10 ml of cold balanced salt solution and a 0.5 ml aliquot of the homogenate is implanted intraperitoneally into each of the test mice. The test compounds are administered intraperitoneally on days 1 through 9 (relative to tumor inoculation) at the indicated doses. The mice are weighed and survivors recorded on a regular basis for 60 days. The median survival time and the ratio of survival time for treated (T)/control (C) animals are calculated. A value of T/C of greater or equal to 125 is considered indicative of significant antitumor activity.
  • All target cells were maintained in RPMI 1640 media supplemented with 5% Fetal Calf Serum (FCS), ITS (Collaborative Research, Cat# 40351), streptomycin (50 ⁇ g/ml), penicillin (50 units/ml), gentamycin sulfate (50 ⁇ g/ml) and glutamine (.03%).
  • FCS Fetal Calf Serum
  • ITS Cold-Rediase
  • streptomycin 50 ⁇ g/ml
  • penicillin 50 units/ml
  • gentamycin sulfate 50 ⁇ g/ml
  • glutamine glutamine
  • DPBS Dulbecco's Phosphate Buffered Saline
  • MoAb monoclonal antibody
  • 0.1 ml of cells was aliquoted in each well of a sterile tissue culture polystyrene 96-well plate. The plates were centrifuged for 5 minutes at 1,000 RPM's and the supernatant was flicked off. Plates were air-dried overnight and may be stored at 4 o C for up to 3 months.
  • Non-specific binding sites were blocked by adding 200 ⁇ l of 1% gelatin in DPBS per well and incubating the plate for 1 hour at 37 o C in a humid incubator. (All subsequent incubations are done under similar conditions).
  • the plates were washed once with 250 ⁇ l of 0.05% TWEEN-20 in DPBS (washing solution) using the automated ELISA washing system from Dynatech (Ultrawash II). Samples to be tested were diluted to make a final concentration of 3 ⁇ g/ml MoAb equivalents in 0.1% gelatin-DPBS. Six additional threefold serial dilutions were prepared from each 3 ⁇ g/ml sample and 100 ⁇ l was added to appropriate wells in triplicate.
  • the bottom row of wells only received 100 ⁇ l of 0.1% gelatin as background. Plates were incubated for 45 minutes and then washed three times. Alkaline phosphatase conjugated affinity purified goat anti-mouse immunoglobulins (Cappel Cat# 8611-0231) was diluted 1:125 in 0.1% gelatin and 100 ⁇ l was added to each well. Plates were incubated for 45 minutes and then washed three times. 200 ⁇ l of p -nitrophenyl phosphate substrate solution (see below) was added to each well. After 45 minutes at room temperature the reaction was stopped by the addition of 50 ⁇ l of 3M NaOH. The absorbance of the contents of each well was read at 405 nm in the automated spectrophotometer from Dynatech (EIA Autoreader # EL-310).
  • the reagents were dissolved by continuous stirring and 1M HCl was added until the pH was 9.8. The total volume was made up to 1 liter with water and filter sterilized with a 0.2 ⁇ filter. The buffer was stored in the dark at 4 o C. Immediately before use, p -nitrophenyl phosphate (Sigma, Cat# 104-40) was dissolved in the 10% diethanolamine buffer (must be at room temperature) to give a final concentration of 1 mg/ml.
  • the % binding was plotted on the non-log scale of a semi-log graph and the MoAb concentration was plotted on the log scale.
  • the BD 50 i.e. dose of antibody needed to give 50% binding
  • Appropriate amounts of target cells in 0.2 ml of 10% FCS media were aliquoted into 4 ml polystyrene tubes. Samples to be tested were diluted to a concentration of 2 ⁇ g/ml MoAb equivalents in 10% FCS media. Five three-fold serial dilutions were prepared from each 2 ⁇ g/ml sample and 0.2 ml was added to each tube in duplicate. Background samples received only cells and media. Cells were incubated at 4 o C for 1 hour, then washed 2 times (all RIA washes were done with a 3 ml volume) with 2% FCS media.
  • Appropriate amounts of target cells in 1 ml of 10% FCS media were aliquoted into 4 ml polystyrene test tubes, centrifuged and supernatant was discarded. Samples to be tested were diluted to make a concentration of 200 ⁇ g/ml MoAb equivalents in 10% FCS media. Five additional five-fold serial dilutions were prepared from each 200 ⁇ g/ml sample and 0.05 ml was added to each tube in duplicate. 0.05 ml of 125 I-MoAb was added to each tube (optimal amount is individually determined for each MoAb and batch). Positive control samples contained cells, media and 125 I-MoAb. Background samples contained non-specific cells, media and 125 I-MoAb. Cells were incubated for 1 hour at 4 o C, washed once with 2% FCS media, twice with PBS, transferred and counted as previously mentioned.
  • the monoclonal antibody conjugates of this invention are active as anticancer agents.
  • the assay described below for assessing in vitro cytotoxicity shows the dramatic preference of the constructs for target cell lines as opposed to non-target cells, and provides a measure of utility of targeted forms of the compounds compared to their non-targeted counterparts.
  • Samples to be tested were diluted to a concentration of 0.2 or 0.02 ⁇ g/ml of parent drug equivalents (starting concentration is dependent on cell line to be tested and potency of the parent drug). Three or four additional five-fold dilutions were prepared from each original sample dilution and 0.2 ml was added to sterile 15 ml polystyrene tubes. At least one similar conjugate consisting of parent drug and an irrelevant MoAb was included in each assay to determine specificity of the relevant conjugate. 10 5 appropriate target cells in 0.2 ml of 10% FCS media were aliquoted into the tubes and vortexed. In addition, an identical test was performed utilizing irrelevant cells as targets to further confirm specificity of relevant conjugate. MoAb controls received only equivalent amounts of MoAb and positive control samples received only 10% FCS media.
  • IC 50 of parent drug IC 50 of test sample x 100 % Cytotoxicity Retained
  • the following assay system was used to measure the in vivo activity of the conjugates of this invention.
  • Burkitt lymphoma (Raji) and myeloma (HS Sultan) cells were harvested from culture flasks and inoculated subcutaneously ( ⁇ 80 x 10 6 Raji cells or 40 x 10 6 HS Sultan cells) into test mice.
  • Solid tumors, ovarian carcinomas (CA73, Ovcar-3), breast carcinoma (MX-1) and colon carcinoma (LS174T) were propagated in athymic mice, removed, cut into 2 mm 3 fragments and implanted subcutaneously into test mice (5-8 fragments per mouse).
  • Drugs, monoclonal antibodies and drug-monoclonal antibody conjugates were administered intraperitoneally once each 3 days for 3 or 5 total injections starting on day 2, 3, 4, 6, 7 or 8 days after tumor implantation.
  • Tumor measurements (the length and width of the tumor) were made by means of a Fowler ultra CAL II electronic caliper each 7 days for 4 to 6 weeks post tumor implantation.
  • Tumor mass in mg was estimated from the formula: Length(mm) x Width(mm) 2
  • Tumor growth inhibition was calculated for each test group on a percent of control [mean mg of treated (T) divided by mean mg of control (C) x 100].
  • T/C value ⁇ 42% in groups with ⁇ 65% surviving animals is considered necessary to demonstrate activity.
  • the hydroxysuccinimide enter described in Example 3 was covalently attached to antibodies under slightly alkaline conditions.
  • the following is a general procedure used to make the antibody conjugates listed in Table 7.
  • Antibody at a concentration of 3-5 mg/ml in phosphate buffer containing 0.1M sodium chloride, pH 7.5 was reacted with a 5-20-fold molar excess of the product from Example 3 with stirring, at room temperature for from 1-4 hours.
  • the conjugated protein was desalted chromatographically and aggregated protein was separated from monomeric material by gel filtration HPLC. Monomeric fractions were pooled and concentrated.
  • Conjugates were analyzed for the presence of aggregates by gel filtration HPLC and for free drug by reverse phase HPLC. Drug loading was determined spectroscopically using the extinction coefficients of both the antibody and the drug to estimate molar concentrations of drug in conjugates.
  • Lym 1 2.8 Lym 2 1.4 B72.3 #1 2.1 #2 2.4 CT-M-01 #1 1.6 #2 3.6 #3 2.5 #4 2.4

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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  • Medicines Containing Plant Substances (AREA)
  • Saccharide Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
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EP90106631A 1989-04-14 1990-04-06 Targeted forms of methyltrithio antitumor agents Expired - Lifetime EP0392384B1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US33932389A 1989-04-14 1989-04-14
US07/339,343 US5053394A (en) 1988-09-21 1989-04-14 Targeted forms of methyltrithio antitumor agents
US339323 1989-04-14
US339343 1994-11-14

Publications (3)

Publication Number Publication Date
EP0392384A2 EP0392384A2 (en) 1990-10-17
EP0392384A3 EP0392384A3 (en) 1991-11-06
EP0392384B1 true EP0392384B1 (en) 1998-02-18

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EP90106631A Expired - Lifetime EP0392384B1 (en) 1989-04-14 1990-04-06 Targeted forms of methyltrithio antitumor agents

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EP (1) EP0392384B1 (xx)
JP (1) JP2951684B2 (xx)
CN (2) CN1046333A (xx)
AT (1) ATE163293T1 (xx)
AU (1) AU633069B2 (xx)
CZ (1) CZ293228B6 (xx)
DE (1) DE69032051T2 (xx)
DK (1) DK0392384T3 (xx)
ES (1) ES2112244T3 (xx)
FI (1) FI100105B (xx)
GR (1) GR3026177T3 (xx)
IL (3) IL115770A (xx)
NO (2) NO176717C (xx)
NZ (1) NZ233148A (xx)
PT (1) PT93716B (xx)
SK (1) SK284270B6 (xx)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5079233A (en) * 1987-01-30 1992-01-07 American Cyanamid Company N-acyl derivatives of the LL-E33288 antitumor antibiotics, composition and methods for using the same
EP0342341A3 (en) * 1988-05-17 1991-07-24 American Cyanamid Company Process for producing antitumor antibiotic ll-e33288gamma2
GB9120467D0 (en) * 1991-09-26 1991-11-06 Celltech Ltd Anti-hmfg antibodies and process for their production
US6015562A (en) * 1992-09-22 2000-01-18 American Cyanamid Company Targeted forms of methyltrithio antitumor agents
US5773001A (en) * 1994-06-03 1998-06-30 American Cyanamid Company Conjugates of methyltrithio antitumor agents and intermediates for their synthesis
US5714586A (en) * 1995-06-07 1998-02-03 American Cyanamid Company Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates
US5712374A (en) * 1995-06-07 1998-01-27 American Cyanamid Company Method for the preparation of substantiallly monomeric calicheamicin derivative/carrier conjugates
US6441163B1 (en) * 2001-05-31 2002-08-27 Immunogen, Inc. Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents
SI3066074T1 (sl) * 2013-11-04 2020-03-31 Pfizer Inc. Intermediati in postopki za sintetizacijo derivatov kaliheamicina
MA45326A (fr) * 2015-10-20 2018-08-29 Genentech Inc Conjugués calichéamicine-anticorps-médicament et procédés d'utilisation
JP6917049B2 (ja) * 2017-02-22 2021-08-11 公立大学法人大阪 特定のサルファイド化合物に結合する抗体及びその使用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE219096T1 (de) * 1987-01-30 2002-06-15 American Cyanamid Co Dihydroderivate der antibiotika vom typ ll-e33288
DE3851682T2 (de) * 1987-10-30 1995-05-04 American Cyanamid Co Targetformer von Antitumor-Methyltrithioagenzien.

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CN1046333A (zh) 1990-10-24
SK284270B6 (sk) 2004-12-01
NO932192D0 (no) 1993-06-14
NO932192L (no) 1990-10-15
CZ293228B6 (cs) 2004-03-17
NO177308C (no) 1995-08-23
IL93733A0 (en) 1990-12-23
FI901866A0 (fi) 1990-04-12
SK188490A3 (en) 2000-08-16
ES2112244T3 (es) 1998-04-01
IL115770A0 (en) 1996-01-19
AU5324190A (en) 1990-11-01
CN1109041C (zh) 2003-05-21
CN1110280A (zh) 1995-10-18
CZ188490A3 (cs) 2000-08-16
NO177308B (no) 1995-05-15
PT93716B (pt) 1996-08-30
NO901655D0 (no) 1990-04-11
GR3026177T3 (en) 1998-05-29
IL93733A (en) 1996-01-19
DK0392384T3 (da) 1998-03-16
NO176717C (no) 1995-05-16
EP0392384A2 (en) 1990-10-17
NO901655L (no) 1990-10-15
EP0392384A3 (en) 1991-11-06
JP2951684B2 (ja) 1999-09-20
AU633069B2 (en) 1993-01-21
IL115770A (en) 1999-03-12
NZ233148A (en) 1996-02-27
NO176717B (no) 1995-02-06
DE69032051T2 (de) 1998-06-10
JPH02292294A (ja) 1990-12-03
PT93716A (pt) 1990-11-20
FI100105B (fi) 1997-09-30
DE69032051D1 (de) 1998-03-26
ATE163293T1 (de) 1998-03-15

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